This invention relates generally to apparatus and methods used for freeze-drying products or specimens. That is, the present invention relates to apparatus and methods for removing a solvent, typically water, from a specimen containing a solvent by first reducing the temperature of the specimen so that the solvent solidifies and then exposing the sample to subatmospheric pressures so that the frozen solvent sublimates with little or no generation of liquid solvent. Specifically, the present invention provides improved methods and apparatus for freeze-drying in which the process can be performed more quickly and more efficiently than conventional processes.
Freeze-drying, which is also known as lyophilization, is the process of removing a solvent, typically water, from a product by sublimation and desorbtion. Though the laymen may associate the freeze-drying process with instant coffee, the process is typically applied to a broad range of medical, biological, and pharmaceutical products, typically for preservation of the product being treated. For example, some pharmaceutical compounds decompose in the presence of water and freeze-drying these compounds improves their stability and shelf life. Many parentereal medications, such as vaccines, proteins, peptides, and antibiotics, have been successfully freeze-dried. Many products in the burgeoning field of biotechnology are also amenable to freeze-drying and new developments in this field will increase the demand for freeze-drying methods and apparatus.
Freeze-drying typically is performed in a three-phase process: freezing, primary drying, and secondary drying. During the freezing phase, the goal is to freeze the solvent, typically water, of the product being treated. Significant supercooling of the liquid solvent may be encountered during the freezing step, so the temperature of the freezing step is typically much lower than the actual freezing temperature of the solvent to ensure that freezing (that is, solidification) of all the solvent present occurs. Cooling to temperatures below the freezing point of the solvent, for example, to temperatures of minus 40 degrees or below, better ensures that the specimen is xe2x80x9cfully frozenxe2x80x9d. That is, cooling to these low temperatures minimizes the presence of any liquid in the specimen, for example, liquid eutectics interstitially located between other solidified components of the specimen, the presence of which can produce inferior freeze-dried products. The rate of cooling will influence the structure of the frozen matrix. The method of cooling will also affect the structure and appearance of the matrix and final product. Thus, in the freeze-drying process the regulation and control of the freezing process is very important to the quality of the resulting freeze-dried substance. According to one aspect of the present invention, the freezing phase of the freeze-drying process can be more efficiently regulated.
In the primary drying phase, the pressure to which the frozen sample is exposed is reduced, and then heat is applied to the product to cause the frozen solvent to sublime, or pass from a solid phase directly to a gaseous phase. The solvent vapor is collected, for example, on the surface of a condenser. The condenser must have sufficient surface area and cooling capacity to hold all of the solvent sublimated from the product sample. In addition, it is preferred that the surface temperature of the condensed solvent be lower than the product temperature. If the temperature of the condensed solvent on the condenser (for example, the ice formed on the condenser coils) is warmer than the product, solvent vapor will tend to flow toward the product and not the condenser and drying will stop. Of course, this is undesirable. According to another aspect of this invention, the location of the condensing surface provides enhanced condensation compared to the prior art.
It is important to control the drying rate and the heating rate during the primary drying phase. If the drying proceeds too rapidly, sublimation can occur too rapidly and the rapid release of gaseous solvent from within the product can violently eject some of the product out the container holding the product and result in unusable product. If the product is heated too rapidly, the product will melt or collapse. This may cause degradation of the product, and will certainly change the physical characteristics of the dried material, making it visually unappealing and harder to reconstitute. While frozen solvent is present, the product must be held below the eutectic temperature or glass transition temperature of the solvent.
After completion of the primary drying phase, there is typically no xe2x80x9cmobilexe2x80x9d liquid solvent remaining in the product. Thus, after the primary drying phase, the temperature of the freeze-dryer, for example, the shelf temperature, may be increased without causing melting. However, there may be immobile, trapped, or xe2x80x9cboundxe2x80x9d liquid solvent still present in the product. Therefore, to remove this bound solvent, the temperature can be increased to desorb the bound liquid solvent, such as the water of crystallization, until the residual liquid solvent content falls to the range required for optimum product stability. This phase of the freeze-drying process is referred to as xe2x80x9csecondary dryingxe2x80x9d. Secondary drying is usually performed at the maximum vacuum that the dryer can achieve, although there are products that benefit from increased pressures also.
Freeze-drying equipment has improved over the years, and, with the advent of automated, sophisticated control mechanisms, freeze-drying equipment has become much easier to use. However, there is still a need to improve the operation and maintainability of prior art freeze-dryers.
One prior art freeze-dryer over which the present invention is an improvement, is the ALPHA 1-2 freeze-dryer manufactured by Martin Christ of Osterode, Germany, for example, the freeze-dryer disclosed in the undated Martin Christ brochure entitled xe2x80x9cALPHA, The Freeze Dryerxe2x80x9d. For example, FIG. 1 of this brochure illustrates a shallow-pan freeze dryer having exposed cooling coils about its internal surface. Not only can the location and configuration of these coils interfere with the handling of specimens and the cleaning of the device shown, but exposed coils such as these are limited to cooling the specimens shown only by means of radiation and convection. This cooling at-a-distance is not as efficient or as effective as cooling by direct thermal contact with the specimen being cooled. In addition, the treatment chambers shown in this brochure typically include a plurality of ports or orifices, for example, for vacuum source access, coolant ingress and egress, and drains, that also require machining during fabrication and maintenance during use.
Regardless of the improvements made, existing methods and equipment for effecting freeze-drying still have limited cooling capacity, require multiple ports in the treatment chamber, and are cumbersome to use due to the presence of exposed cooling coils, among other disadvantages. The present invention provides enhanced methods and apparatus for freeze-drying which overcome these and other limitations of the prior art.
The present invention provides methods and apparatus which address many of the limitations of prior art methods and apparatus. Though the present invention can be adapted for large commercial processing, the present invention is typically applicable to xe2x80x9cbench-topxe2x80x9d applications, for example, for research or academic laboratories. The present invention can be designed to have an xe2x80x9cice capacityxe2x80x9d of up to about 100 kg or more, but, typically the present invention has a capacity of less than 50 kg, for example, between about 1 and 10 kg. One embodiment of the present invention is a freeze-dryer comprising: a chamber having a cover, side walls and a thermally-conductive base, the base having an interior surface and a conduit therein; a specimen holder disposed in the chamber for holding a specimen to be freeze-dried, the specimen holder having a support tube slidably engaging the conduit so as to be selectively moveable between a position in which the specimen holder is in contact with the interior surface of the base and one or more positions in which the specimen holder is not in contact with the interior surface of the base; means mounted below the interior surface of the base for cooling the specimen; and means for reducing the pressure in the chamber by drawing a vacuum.
According to the present invention, an aspect that clearly distinguishes the present invention from the prior art, means for cooling the specimen cools the specimen primarily by conduction. Conduction cooling is much more efficient than radiation cooling or connective cooling as practiced in the prior art. For example, prior art freeze dryers which do not provide conduction cooling are typically limited to cooling samples to only minus 37 degrees C. in a single stage of cooling. The freeze dryer of the present invention can cool samples to about minus 40 degrees C. or about minus 50 degrees C., or to even colder temperatures in a single stage of cooling. For multiple-stage cooling, the present invention can cool to colder temperatures, and these colder temperatures can be typically 25-30% colder temperatures than the prior art for multiple-stage cooling. The means for reducing the pressure in the chamber may be any conventional means, but is typically a conventional vacuum pump operatively connected to the chamber.
Another embodiment of this present invention a method for freeze-drying a specimen containing a solvent in a chamber having a base with an interior surface, the chamber having a thermally-conductive specimen holder moveable between a position in contact with the interior surface of the base and one or more positions not in contact with the interior surface of the base; means for cooling mounted beneath the interior surface of the base; and a source of vacuum operatively connected to the chamber for reducing the pressure in the chamber, comprising: positioning the specimen holder so that it contacts the interior surface of the base of the chamber; placing the specimen on the specimen holder; operating the cooling means so as to cool the specimen at least by conduction to a temperature below the freezing temperature of the solvent; moving the specimen holder to a position out of contact with the interior surface of the base of the chamber; and reducing the pressure in the chamber by activating the source of vacuum to obtain a pressure in the chamber at which the solvent will sublime to produce a freeze-dried specimen. The specimen may be cooled by the cooling means of the chamber or may be cooled externally, for example, in a separate freezer. The method of the invention can be practiced using a specimen holder which includes a perforated support tube that slidably engages the conduit in the base of the chamber and wherein the pressure reducing step is practiced by drawing at least some of the vacuum through at least one of the support tube perforations. The invention may further include, prior to or simultaneously with the pressure reducing step, heating the specimen to promote sublimation of the solvent and condensing the solvent in the chamber.
One advantage of the present invention is that the freezing and drying steps can be performed in the same chamber, without requiring separate devices or chambers to carry out the freeze-drying process. In addition, according to the present invention, samples do not have to be individually handled, which is convenient for the operator and avoids undesirable melting or contamination of the sample due to human or instrument contact.
Another embodiment of the invention is a method for freeze-drying a specimen containing a solvent in a chamber having a moveable specimen holder mounted on a perforated tube, the tube slidably mounted in a conduit in the base of the chamber; means for cooling the specimen mounted beneath the base of the chamber; and a source of vacuum operatively connected to the conduit in the base of the chamber for reducing the pressure in the chamber, comprising: positioning the specimen holder so that it contacts the base of the chamber; placing the specimen on the specimen holder; cooling the specimen at least by conduction to a temperature of at least about minus 40 degrees C. using the cooling means; supporting the specimen holder above and out of contact with the base of the chamber; and reducing the pressure in the chamber by activating the source of vacuum and drawing a vacuum through the conduit and at least one of the tube perforations to obtain a pressure in the chamber at which the solvent will sublime to produce a freeze-dried specimen.
A still further embodiment of the invention is a specimen holder for use in a freeze-dryer of the type having a treatment chamber having a base and a conduit therein, comprising: a specimen tray having a top and a bottom for holding a specimen; a cylindrical tube mounted to the bottom of the specimen tray having at least one perforation, the cylindrical tube adapted to slidably engage the conduit in the base of the chamber; and means for supporting the specimen tray above the base of the chamber. Typically, the cylindrical tube is right circular cylindrical in shape though any conventional cross-section may be used. In addition, according to this embodiment, the at least one perforation in the cylindrical tube is a plurality of perforations. Also, the plurality of perforations may comprise at least one perforation having a first diameter and at least one perforation having a second diameter, smaller than the first diameter. The at least one perforation may also be a plurality of perforations equally spaced along the tube or the at least one perforation may be a first perforation proximal the bottom of the plate and having a first diameter, and a set of equally-spaced perforations distal the bottom of the plate having a second diameter, smaller than said first diameter. The means for supporting the plate may comprise a wire spring clip.
A further aspect of the present invention includes a freeze dryer for treating a specimen containing a solvent, comprising: a chamber having a cover, side walls and a thermally-conductive base, the base having an interior surface; means for reducing the pressure in the chamber whereby at least some of the solvent in the specimen sublimes to form a gaseous solvent; and means mounted below the interior surface of the base for cooling the interior surface of the base to provide a condensing surface for the solvent.
A further aspect of the present invention includes a freeze-dryer, for treating a specimen containing a solvent, comprising: a chamber for holding the specimen, the chamber having a cover, side walls and a thermally-conductive base, the base having an interior surface; means for a reducing the pressure in the chamber whereby at least some gaseous solvent is formed; means mounted below the interior surface for cooling the interior surface whereby at least some solvent solidifies on the interior surface during treatment; and means for deflecting the interior surface whereby the at least some solidified solvent is dislodged from the interior surface to facilitate removal of the solidified solvent from the chamber.
A still further aspect of the present invention is a method for freeze-drying a specimen containing a solvent in a chamber having a base with thermally-conductive, deflectable interior surface; means for cooling mounted beneath the interior surface of the base; and a source of vacuum operatively connected to the chamber for reducing the pressure in the chamber, comprising: locating the specimen in the chamber; reducing the pressure in the chamber by activating the source of vacuum whereby at least some solvent sublimes; cooling the interior surface of the base via the means for cooling; condensing at least some solvent on the cooled interior surface; and deflecting the interior surface of the base whereby at least some solid condensate is dislodged from the interior surface.
These and other aspects of the present invention will become more apparent upon review of the attached drawings, description below, and attached claims.